Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma

MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and -181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensitive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and -181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and -181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection.     

Drinking and Breathing: Solvent Coordination-driven Plasticity of IRMOF-9

The coordination chemistry of Metal-Organic Frameworks is one key aspect when their applications and performances enhancement are pursued. This is usually investigated while cation exchanges or functionalisation reactions on open metal sites are involved. In this work we present a rare case of solvent coordination-induced breathing behaviour of a renowned Zn-based MOF, namely IRMOF-9, whose structural flexibility allows its framework topology to be retained upon dramatic coordination changes on their inorganic nodes. These are observed to accept from one to three additional coordination bonds from solvent molecules, depending on the coordination power of these latter and on temperature conditions. Structural studies by Single Crystal X-Ray Diffraction afforded precious insights on the occurring of such coordinative changes, suggesting that solvent molecules which dynamically bind the metal atoms are capable to play a decisive role in the final geometry of the framework.     

Low voltage water electrolysis: Decoupling hydrogen production using bioelectrochemical system

Decoupling water electrolysis using mediator is an interesting way to produce pure hydrogen. The present work validates the proof of concept of decoupled electrolyser associated with a bioelectrochemical system (MFC-DES) through a redox flow mediator (potassium hexacyanoferrate (KHCF)). Low voltage (1 V) hydrogen production was achieved with a current density up to 25 mA cm^?2. Regeneration of the mediator was performed by glucose fed microbial fuel cells. The oxidation rate of KHCF in the electrolyser is, at least, an order of magnitude higher than the reduction rate in MFC cascade fed system. MFC-DES is thus a promising set up as it desynchronizes limited microbial rate and hydrogen production, generate value from wastewater and reduce energetic cost of water electrolysis.     

Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use-Dependent Inhibitors of Voltage-Gated Sodium Channels

Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated in vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation.     

Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

In this study, we report the effects of caffeine on angiogenesis in zebrafish embryos both during normal development and after exposure to Fibroblast Growth Factor 2 (FGF2). As markers of angiogenesis, we measured the length and width of intersegmental vessels (ISVs), performed whole-mount in situ hybridization with fli1 and cadh5 vascular markers, and counted the number of interconnecting vessels (ICVs) in sub-intestinal venous plexus (SIVP). In addition, we measured angiogenesis after performing zebrafish yolk membrane (ZFYM) assay with microinjection of fibroblast growth factor 2 (FGF2) and perivitelline tumor xenograft assay with microinjection of tumorigenic FGF2-overexpressing endothelial (FGF2-T-MAE) cells. The results showed that caffeine treatment causes a shortening and thinning of ISVs along with a decreased expression of the vascular marker genes and a decrease in the number of ICVs in the SIVP. Caffeine was also able to block angiogenesis induced by exogenous FGF2 or FGF2-producing cells. Overall, our results are suggestive of the inhibitory effect of caffeine in both direct and indirect angiogenesis.     

Ageing Causes Ultrastructural Modification to Calcium Release Units and Mitochondria in Cardiomyocytes

Ageing is associated with an increase in the incidence of heart failure, even if the existence of a real age-related cardiomyopathy remains controversial. Effective contraction and relaxation of cardiomyocytes depend on efficient production of ATP (handled by mitochondria) and on proper Ca²⁺ supply to myofibrils during excitation–contraction (EC) coupling (handled by Ca²⁺ release units, CRUs). Here, we analyzed mitochondria and CRUs in hearts of adult (4 months old) and aged (≥24 months old) mice. Analysis by confocal and electron microscopy (CM and EM, respectively) revealed an age-related loss of proper organization and disposition of both mitochondria and EC coupling units: (a) mitochondria are improperly disposed and often damaged (percentage of severely damaged mitochondria: adults 3.5 ± 1.1%; aged 16.5 ± 3.5%); (b) CRUs that are often misoriented (longitudinal) and/or misplaced from the correct position at the Z line. Immunolabeling with antibodies that mark either the SR or T-tubules indicates that in aged cardiomyocytes the sarcotubular system displays an extensive disarray. This disarray could be in part caused by the decreased expression of Cav-3 and JP-2 detected by western blot (WB), two proteins involved in formation of T-tubules and in docking SR to T-tubules in dyads. By WB analysis, we also detected increased levels of 3-NT in whole hearts homogenates of aged mice, a product of nitration of protein tyrosine residues, recognized as marker of oxidative stress. Finally, a detailed EM analysis of CRUs (formed by association of SR with T-tubules) points to ultrastructural modifications, i.e., a decrease in their frequency (adult: 5.1 ± 0.5; aged: 3.9 ± 0.4 n./50 μm²) and size (adult: 362 ± 40 nm; aged: 254 ± 60 nm). The changes in morphology and disposition of mitochondria and CRUs highlighted by our results may underlie an inefficient supply of Ca²⁺ ions and ATP to the contractile elements, and possibly contribute to cardiac dysfunction in ageing.     

Synthesis and Biological Evaluation of New Geiparvarin Derivatives

New geiparvarin derivatives modified at the alkenyloxy bridge, where the 3′‐methyl group was replaced by a hydrogen atom, were synthesized and evaluated against a panel of human tumor cell lines in vitro. Compounds (R)‐ 4 and (R)‐ 5 show greater inhibitory activity toward cell growth than the parent geiparvarin.

     

Mesoporous multifunctional upconversion luminescent and magnetic "nanorattle" materials for targeted chemotherapy

Nanorattles consisting of hydrophilic, rare-earth-doped NaYF(4) shells each containing a loose magnetic nanoparticle were fabricated through an ion-exchange process. The inner magnetic Fe(3)O(4) nanoparticles are coated with a SiO(2) layer to avoid iron leaching in acidic biological environments. This multifunctional mesoporous nanostructure with both upconversion luminescent and magnetic properties has excellent water dispersibility and a high drug-loading capacity. The material emits visible luminescence upon NIR excitation and can be directed by an external magnetic field to a specific target, making it an attractive system for a variety of biological applications. Measurements on cells incubated with the nanorattles show them to have low cytotoxicity and excellent cell imaging properties. In vivo experiments yield highly encouraging tumor shrinkage with the antitumor drug doxorubicin (DOX) and significantly enhanced tumor targeting in the presence of an applied magnetic field.     

Encapsulating Eu3+ complex doped layers to improve Si‐based solar cell efficiency

This paper reports the electrical characterization of commercially available crystalline silicon solar cells encapsulated with poly‐vinylacetate doped with different Eu³⁺ organic complexes. The inclusion of these complexes in the encapsulating matrix allows down‐shifting of the solar spectrum components below 420 nm toward the maximum quantum efficiency of the solar cells. This effect has been proven under Air Mass 1·5 conditions (simulating terrestrial applications) where an increase of the total power delivered by the encapsulated cells has been observed. Moreover, this enhancement has been obtained using very low percentage by weight of organolanthanide dopants, allowing a reduction in the Watt peak price. At higher concentrations a strong quenching of the energy transfer from the organic antenna to the lanthanide ion has been observed. Copyright © 2009 John Wiley & Sons, Ltd.